This invention relates to novel purine nucleosides containing the 2'-deoxy-2'-fluoro-.beta.-D-arabinofuranosyl moiety and potentially useful as antiparasitic agents, especially against Leishmania tropica.
The synthesis of 9-(2'-deoxy-2'-fluoro-.beta.-D-arabino-furanosyl)adenine was reported from our laboratory as an analog of the antitumor and antiviral naturally-occurring nucleoside 9-(.beta.-D-arabinofuranosyl)adenine (ara-A) [Wright et al., J. Org. Chem., 34, 2632 (1969)]. The synthesis consists of a multistep preparation of a 2-deoxy-2-fluoro-D-arabinofuranose derivative from D-xylose, and the 2-fluoro sugar is condensed with 2,6-dichloropurine by the fusion method, followed by multistep conversion of the purine into adenine.
Subsequently, 1-(2'-deoxy-2'-fluoro-.beta.-D-arabinofuranosyl)cytosine (FAC) was synthesized in our laboratory by condensation of an appropriate sugar halide and cytosine by the silyl procedure, and FAC was evaluated for its antitumor activity [Wilson et al., J. Med. Chem., 13, 369 (1970)]. FAC was found to have a growth-inhibitory effect comparable with that of 1-(.beta.-D-arabinofuranosyl)cytosine (ara-C) and 1-(.beta.-D-arabinofuranosyl)-5-fluorocytosine (ara-FC) against L-1210 mouse leukemic cells in tissue culture.
We have since developed a more elegant and effective method for preparation of the 2-fluoro-arabinose from D-glucose [Reichman et al., Carbohyd. Res., 42, 233 (1975)] and prepared a number of 5-substituted-uracil and -cytosine nucleosides as potential antiviral and/or anticancer agents [Lopez et al., U.S. Pat. No. 4,171,429 (1979)]. Many pyrimidine nucleosides containing the 2'-fluoro-.beta.-D-arabinofuranosyl moiety showed excellent antiherpesvirus activity [Fox et al., "Herpesvirus, Clinical, Pharmacological and Basic Aspects;" Shiota et al., eds; Excerpta Medica: Amsterdam, 1982; p.135] and some showed good antitumor activity [Burchenal et al., Cancer Res., 42, 2598 (1982)].
No purine nucleoside containing the 2'-fluoro-.beta.-D-arabinofuranosyl moiety has been reported except the adenine nucleoside synthesized in our laboratory [Wright et al., loc. cit.], and no biological activity of the adenine nucleoside has been reported.